D-amphetamine compounds, compositions, and processes for making and using the same
Inventors
Guenther, Sven • Chi, Guochen • Mickle, Travis
Assignees
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Publication Number
US-11174229-B2
Publication Date
2021-11-16
Expiration Date
Abstract
Disclosed are d-amphetamine compounds and compositions comprising at least one organic acid covalently bound to d-amphetamine, having the structure of a salt thereof, a derivative thereof, or a combination thereof. Methods of making and using the same are also disclosed.
Core Innovation
The disclosed subject matter relates to d-amphetamine prodrug/conjugate compounds in which d-amphetamine is covalently bound to an organic acid moiety, including Formula I and related formula variants. The compounds include substituent definitions for X and Y, with X selected from esters, carboxylic acids, amino acids, amino acid residues, amides, and derivatives thereof, and Y selected from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle.
Exemplary conjugates are provided, including AMP-CO2CH2-nicotinate(Et) and nicotinoyl conjugates with amino-acid-derived groups such as Val, Ser, and Ala, including specific named derivatives. Pharmaceutically acceptable salts of these compounds are also disclosed, together with stereoisomer mixtures when a chiral center is present at the carbon attached to Y.
The invention also encompasses pharmaceutical compositions and dosage formulations using the disclosed compounds and their pharmaceutically acceptable salts, including oral and suppository dosage forms, oral slow/sustained release through hydrolysis of the covalent linkage after oral administration, unit dose ranges, and the possibility of including other pharmacological substances together with the disclosed compounds. A kit format is described that includes individual unit doses of a composition comprising at least one of the disclosed compounds, optionally as a pharmaceutical salt and/or in combination.
A method is described for treating CNS stimulation/neurotransmitter uptake disorders, and the document also addresses abuse potential by describing resistance to abuse by injection/intranasal routes and maintenance of effects after crushing of the controlled-release component. Performance and abuse-potential expectations are described using pharmacokinetic comparisons relative to unconjugated d-amphetamine, including stated comparisons for similar or decreased AUC and/or Cmax and stated reductions under certain administration routes.
Claims Coverage
The claim coverage centers on Formula I compound structure with X and Y substituent classes, pharmaceutically acceptable salt coverage, dosage and oral solid form scope, comparative pharmacokinetic constraints, and optional combination with specified active agents. The independent claim concepts also include kit-based unit-dose pharmaceutical presentations for selected structural groups.
Formula I conjugate structure with defined X and Y classes
A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, where X is selected from esters, carboxylic acids, amino acids, amino acid residues, amides, and derivatives thereof with amide substituent limitations, and where Y is selected from hydrogen, alkenyl, alkoxy, alkyl, alkynyl, aryl, substituted aryl, alkylaryl, cycloalkenyl, cycloalkyl, cycloalkynyl, heteroalkyl, heteroaryl, and heterocycle.
Pharmaceutically acceptable salt selection from a named list
The compound is in a pharmaceutically acceptable salt form selected from specified named salts, including acetate, aspartate, besylate, citrate, hydrochloride, sulfate, and many other listed counterions, or mixtures thereof.
Unit-dose compound amount range
A composition wherein the compound is present at a dose amount between about 0.1 mg and about 2000 mg per unit dose.
Oral solid dosage forms
An oral administration dosage form selected from solid forms including tablets, capsules, caplets, soft gels, suppositories, troches, lozenges, oral powders, and oral films, and including related listed dosage forms.
Equimolar oral pharmacokinetic AUC constraint versus unconjugated d-amphetamine
A composition where, when orally administered at equimolar doses, the compound yields similar or decreased AUC versus unconjugated d-amphetamine.
Combination with one or more specified active agents
A composition including, in addition to the claimed composition, one or more specified active agents, including methylphenidate, aripiprazole, atomoxetine, baclofen, clonidine, and others, or additional amphetamine, in any combination.
Pharmaceutical dosing kit with individual unit doses for a selected-structure compound group
A kit containing individual doses of a pharmaceutical composition that includes at least one compound of claim 6 (optionally as a pharmaceutical salt and/or in combination), where each dose provides a therapeutically effective amount.
Pharmaceutical dosing kit with individual unit doses for a selected-structure compound group
A kit comprising individual unit doses of a therapeutically effective amount of a composition comprising at least one compound of claim 8 and/or a pharmaceutical salt thereof, or combinations thereof.
Compound structure selected from a specified group
A compound having a structure selected from the group consisting of the specified group, with the group details not provided in the supplied text.
Compound structure selected from another specified group
A compound having a structure selected from the group consisting of the specified group, with the group details not provided in the supplied text.
Pharmaceutical dosing kit with individual unit doses and therapeutically effective amount
A pharmaceutical kit containing individual doses of a pharmaceutical composition that includes at least one compound corresponding to the independent claim, optionally as a pharmaceutical salt and/or as a combination, where each dose is present in a therapeutically effective amount.
Overall, the claim coverage is directed to Formula I amphetamine conjugate scaffold definitions with salt, dosage, and oral form constraints; comparative pharmacokinetic performance versus unconjugated d-amphetamine; optional combination therapy with specified active agents; and unit-dose kit presentations for selected structural groups.
Stated Advantages
Reduced abuse potential.
Extended release.
Reduced released d-amphetamine upon parenteral routes.
Similar or decreased AUC versus unconjugated d-amphetamine when orally administered at equimolar doses.
Unexpectedly different or improved exposure versus analogous isonicotinoyl-containing conjugates.
Reduced blood-level spikes to lessen rebound effects.
Reduced cardiovascular stress.
Reduced abuse potential, including resistance to abuse by injection/intranasal routes.
Maintenance of performance after crushing of the controlled-release component.
Documented Applications
CNS stimulation therapy for attention-deficit hyperactivity disorder (ADHD).
CNS stimulation therapy for Tourette syndrome.
Method of treating CNS stimulation/neurotransmitter uptake disorders, including ADHD, narcolepsy, sleep disorder, obesity, depression, bipolar disorder, autism spectrum disorder, Asperger's disorder, pervasive developmental disorder, chronic fatigue syndrome, insomnia, schizophrenia, major depressive disorder, postural orthostatic tachycardia syndrome, Tourette syndrome, nervous tics, substance use disorder, and lethargy.
Oral slow/sustained release therapeutic delivery via hydrolysis of the covalent linkage after oral administration.
Therapeutic use in dosage forms and compositions for administration, including oral and suppository dosage forms.
Abuse-potential mitigation use case addressing resistance to abuse routes such as injection/intranasal and after crushing.
Pharmaceutical dosing kit use case providing individual unit doses of therapeutically effective amounts for the claimed compounds.
Oral, intravenous, and intranasal pharmacokinetic use in rats, with reported Cmax, AUC, and Tmax values for d-amphetamine conjugates.
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